Recent Submissions

  • Journal Article

    Flow-controlled ventilation during ear, nose and throat surgery 

    Schmidt, Johannes; Günther, Franziska; Weber, Jonas; Wirth, Steffen; Brandes, Ivo; Barnes, Tom; Zarbock, Alexander; Schumann, Stefan; Enk, Dietmar
    European Journal of Anaesthesiology 2019; 36(5) p.327-334
    BACKGROUND: Flow-controlled ventilation (FCV) is a new mechanical ventilation mode that maintains constant flow during inspiration and expiration with standard tidal volumes via cuffed narrow-bore endotracheal tubes. Originating in manually operated 'expiratory ventilation assistance', FCV extends this technique by automatic control of airway flow, monitoring of intratracheal pressure and control of peak inspiratory pressure and end-expiratory pressure. FCV has not yet been described in a clinical study. OBJECTIVE: The aim of this study was to provide an initial assessment of FCV in mechanically ventilated patients undergoing ear, nose and throat surgery and evaluate its potential for future use. DESIGN: An observational study. SETTING: Two German academic medical centres from 24 November 2017 to 09 January 2018. PATIENTS: Consecutive patients (≥ 18 years) scheduled for elective ear, nose and throat surgery. Exclusion criteria were planned laser surgery, intended fibreoptic awake intubation, emergency procedures, increased risk of aspiration, American Society of Anesthesiologists (ASA) physical status more than III and chronic obstructive pulmonary disease classified as GOLD stage more than II. INTERVENTION: Peri-operative use of FCV provided by a new type of ventilator (Evone) via a narrow-bore endotracheal tube (Tritube). MAIN OUTCOME MEASURES: Minute volume, respiratory rate, intratidal tracheal pressure amplitude (Δp) and end-tidal CO2 (PetCO2) were recorded every 5 min. All adverse events were noted. Data are presented as median [IQR]. RESULTS: Sixteen patients provided 15 evaluable data sets. A minute volume of 5.0 [4.4 to 6.4] l min and a respiratory rate of 9 [8 to 11] min generated a PetCO2 of 4.9 [4.8 to 5.0] kPa. Δp was 10 [9 to 12] cmH2O. Five adverse events were recorded: a tube obstruction due to airway secretions and four tube dislocations (two attributed to coughing, two not study-related). CONCLUSION: FCV achieves adequate PetCO2 levels with minute volume and Δp in the normal range. Tritube's high flow resistance may increase the likelihood of tube dislocations if the patient coughs. Although further evaluation is necessary, FCV provides a new option for short-term mechanical ventilation. The successful operation of FCV with narrow-bore tubes contributes to the armamentarium for airway management.
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  • Journal Article

    The Role of Proopiomelanocortin and α-Melanocyte-Stimulating Hormone in the Metabolic Syndrome in Psychiatric Disorders: A Narrative Mini-Review 

    Raue, Stefan; Wedekind, Dirk; Wiltfang, Jens; Schmidt, Ulrike
    Frontiers in Psychiatry 2019; 10: Art. 834
    The metabolic syndrome (MetS) comprises abdominal obesity, preclinical or full diabetes type 2, arterial hypertension, and dyslipidemia and affects a significant proportion of the general population with a remarkably higher prevalence in patients suffering from psychiatric disorders. However, studies exploring the pathogenetic link between MetS and psychiatric diseases are rare. Here, we aim to narrow this gap in knowledge by providing a narrative review on this topic that focuses on two psychiatric diseases, namely on schizophrenia and posttraumatic stress disorder (PTSD) since we assume them to be associated with two different main causalities of MetS: in schizophrenia, MetS evidently develops or aggravates in response to antipsychotic drug treatment while it assumingly develops in response to stress-induced endocrine and/or epigenetic alterations in PTSD. First, we compared the prevalences of MetS and associated pathologies (which we took from the latest meta-analyses) among different psychiatric disorders and were surprised that the prevalences of arterial hypertension and hyperglycemia in PTSD almost doubles those of the other psychiatric disorders. Next, we performed a literature search on the neurobiology of MetS and found numerous articles describing a role for proopiomelanocortin (POMC) in MetS. Thus, we concentrated further analysis on POMC and one of its downstream effector hormones, α-melanocyte-stimulating hormone (α-MSH). We found some evidence for a role of POMC in both PTSD and schizophrenia, in particular in antipsychotic-induced MetS, as well as for α-MSH in schizophrenia, but, surprisingly, no study on α-MSH in PTSD. Taken together, our synopsis reveals, first, a potential interaction between the POMC system and stress in the assumingly at least partially shared pathogenesis of psychiatric disorders and MetS, second, that modulation of the POMC system, in particular of the melanocortin 3 and 4 receptors, might be a promising target for the treatment of MetS and, third, that the DNA methylation status of POMC might speculatively be a promising biomarker for MetS in general and, possibly, in particular in the context of stress-related psychiatric conditions such as PTSD. To best of our knowledge, this is the first review on the role of the POMC system in MetS in psychiatric disorders.
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  • Journal Article

    Functional MRI in patients with detrusor sphincter dyssynergia: Is the neural circuit affected? 

    Seseke, Sandra; Leitsmann, Conrad; Hijazi, Sameh; Trojan, Lutz; Dechent, Peter
    Neurourology and Urodynamics 2019; 38(8) p.2104-2111
    AIMS: In recent years, the human brain-bladder control network has been visualized in different functional magnetic resonance imaging (fMRI) studies. The role of the brainstem and suprapontine regions has been elucidated. Especially the pontine region and the periaqueductal gray, as the central structures of the micturition circuit, were demonstrated. Detrusor sphincter dyssynergia (DSD) is a common problem in patients with neurological diseases. Residual urine and consecutive urinary tract infections with the risk of kidney damage remain a problem. In the present study, we used fMRI of the brain to compare the activation sites of patients with DSD with those of our previously published healthy controls with special emphasis on the brainstem region. METHODS: fMRI was performed in 11 patients with DSD who had an urge to void due to a filled bladder. In a nonvoiding model, they were instructed to contract or to relax the pelvic floor muscles repetitively. RESULTS: In patients with DSD, we could reproduce the activation sites found in healthy subjects, showing the regions in the brainstem as well as the other micturition-related areas. The activation of the pontine region was more rostral/dorsal compared with the healthy volunteers. CONCLUSION: Interestingly, we detected the well-known activation in the pontine region in the patients in the dorsal/rostral part compared with the more ventral activation in the healthy volunteers, suggesting that the L-region of the pontine micturition center is more prominent in cases of DSD.
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  • Journal Article

    Atrial fibrillation is frequent but does not affect risk stratification in pulmonary embolism 

    Ebner, M.; Rogge, N. I. J.; Parwani, A. S.; Sentler, C.; Lerchbaumer, M. H.; Pieske, B.; Konstantinides, S. V.; Hasenfuß, G.; Wachter, R.; Lankeit, M.
    Journal of Internal Medicine
    BACKGROUND: Although prior studies indicate a high prevalence of atrial fibrillation (AF) in patients with pulmonary embolism (PE), the exact prevalence and prognostic impact are unknown. METHODS: We aimed to investigate the prevalence, risk factors and prognostic impact of AF on risk stratification, in-hospital adverse outcomes and mortality in 528 consecutive PE patients enrolled in a single-centre registry between 09/2008 and 09/2017. RESULTS: Overall, 52 patients (9.8%) had known AF and 57 (10.8%) presented with AF on admission; of those, 34 (59.6%) were newly diagnosed with AF. Compared to patients with no AF, overt hyperthyroidism was associated with newly diagnosed AF (OR 7.89 [2.99-20.86]), whilst cardiovascular risk comorbidities were more frequently observed in patients with known AF. Patients with AF on admission had more comorbidities, presented more frequently with tachycardia and elevated cardiac biomarkers and were hence stratified to higher risk classes. However, AF on admission had no impact on in-hospital adverse outcome (8.3%) and in-hospital mortality (4.5%). In multivariate logistic regression analyses corrected for AF on admission, NT-proBNP and troponin elevation as well as higher risk classes in risk assessment models remained independent predictors of an in-hospital adverse outcome. CONCLUSION: Atrial fibrillation is a frequent finding in PE, affecting more than 10% of patients. However, AF was not associated with a higher risk of in-hospital adverse outcomes and did not affect the prognostic performance of risk assessment strategies. Thus, our data support the use of risk stratification tools for patients with acute PE irrespective of the heart rhythm on admission.
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  • Journal Article

    Absolute quantification of donor‐derived cell‐free DNA as a marker of rejection and graft injury in kidney transplantation: Results from a prospective observational study 

    Oellerich, Michael; Shipkova, Maria; Asendorf, Thomas; Walson, Philip D.; Schauerte, Verena; Mettenmeyer, Nina; Kabakchiev, Mariana; Hasche, Georg; Gröne, Hermann‐Josef; Friede, Tim; et al.
    Wieland, EberhardSchwenger, VedatSchütz, EkkehardBeck, Julia
    American Journal of Transplantation 2019; 19(11) p.3087-3099
    Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma (dd-cfDNA[cp/mL]) was compared to dd-cfDNA fraction (dd-cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy-proven rejection (BPR). dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd-cfDNA(cp/mL) (AUC = 0.83) compared to dd-cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd-cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8 μg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies.
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  • Journal Article

    Production of highly concentrated and hyperpolarized metabolites within seconds in high and low magnetic fields 

    Korchak, Sergey; Emondts, Meike; Mamone, Salvatore; Blümich, Bernhard; Glöggler, Stefan
    Physical Chemistry Chemical Physics 2019; 21(41) p.22849-22856
    Hyperpolarized metabolites are very attractive contrast agents for in vivo magnetic resonance imaging studies enabling early diagnosis of cancer, for example. Real-time production of concentrated solutions of metabolites is a desired goal that will enable new applications such as the continuous investigation of metabolic changes. To this end, we are introducing two NMR experiments that allow us to deliver high levels of polarization at high concentrations (50 mM) of an acetate precursor (55% 13C polarization) and acetate (17% 13C polarization) utilizing 83% para-state enriched hydrogen within seconds at high magnetic field (7 T). Furthermore, we have translated these experiments to a portable low-field spectrometer with a permanent magnet operating at 1 T. The presented developments pave the way for a rapid and affordable production of hyperpolarized metabolites that can be implemented in e.g. metabolomics labs and for medical diagnosis.
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  • Journal Article

    Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2019 

    Haehling, Stephan; Morley, John E.; Coats, Andrew J. S.; Anker, Stefan D.
    Journal of Cachexia, Sarcopenia and Muscle 2019; 10(5) p.1143-1145
    This article details an updated version of the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM) and its two daughter journals JCSM Rapid Communication and JCSM Clinical Reports. We request of all author sending to the journal a paper for consideration that at the time of submission to JCSM, the corresponding author, on behalf of all co-authors, needs to certify adherence to these principles. The principles are as follows: all authors listed on a manuscript considered for publication have approved its submission and (if accepted) approve publication in JCSM as provided; each named author has made a material and independent contribution to the work submitted for publication; no person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript; the submitted work is original and is neither under consideration elsewhere nor that it has been published previously in whole or in part other than in abstract form; all authors certify that the submitted work is original and does not contain excessive overlap with prior or contemporaneous publication elsewhere, and where the publication reports on cohorts, trials, or data that have been reported on before the facts need to be acknowledged and these other publications must be referenced; all original research work has been approved by the relevant bodies such as institutional review boards or ethics committees; all relevant conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively, and relevant sources of funding of the research in question have been duly declared in the manuscript; the manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true. If any of the aforementioned statements ceases to be true, the authors have a duty to notify as soon as possible the Editors of JCSM, JCSM Rapid Communication, and JCSM Clinical Reports, respectively, so that the available information regarding the published article can be updated and/or the manuscript can be withdrawn.
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  • Journal Article

    Open access efforts begin to bloom: ESC Heart Failure gets full attention and first impact factor 

    Anker, Stefan D.; Haehling, Stephan; Papp, Zoltan
    ESC Heart Failure 2019; 6(5) p.903-908
    In 2014, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) founded the first open access journal focusing on heart failure, called ESC Heart Failure (ESC-HF). In the first 5 years, in ESC-HF we published more than 450 articles. Through ESC-HF, the HFA gives room for heart failure research output from around the world. A transfer process from the European Journal of Heart Failure to ESC-HF has also been installed. As a consequence, in 2018 ESC-HF received 289 submissions, and published 148 items (acceptance rate 51%). The journal is listed in Scopus since 2014 and on the PubMed website since 2015. In 2019, we received our first impact factor from ISI Web of Knowledge / Thomson-Reuters, which is 3.407 for 2018. This report reviews which papers get best cited. Not surprisingly, many of the best cited papers are reviews and facts & numbers mini reviews, but original research is also well cited.
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  • Journal Article

    Reactivity of the reward system in artists during acceptance and rejection of monetary rewards 

    Goya-Maldonado, Roberto; Keil, Maria; Brodmann, Katja; Gruber, Oliver
    Creativity Research Journal 2018; 30(2) p.172-178
    creativity, reward, artist, fMRI
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  • Journal Article

    CaosDB—Research Data Management for Complex, Changing, and Automated Research Workflows 

    Fitschen, Timm; Schlemmer, Alexander; Hornung, Daniel; tom Wörden, Henrik; Parlitz, Ulrich; Luther, Stefan
    Data 2019; 4(2)
    We present CaosDB, a Research Data Management System (RDMS) designed to ensure seamless integration of inhomogeneous data sources and repositories of legacy data in a FAIR way. Its primary purpose is the management of data from biomedical sciences, both from simulations and experiments during the complete research data lifecycle. An RDMS for this domain faces particular challenges: research data arise in huge amounts, from a wide variety of sources, and traverse a highly branched path of further processing. To be accepted by its users, an RDMS must be built around workflows of the scientists and practices and thus support changes in workflow and data structure. Nevertheless, it should encourage and support the development and observation of standards and furthermore facilitate the automation of data acquisition and processing with specialized software. The storage data model of an RDMS must reflect these complexities with appropriate semantics and ontologies while offering simple methods for finding, retrieving, and understanding relevant data. We show how CaosDB responds to these challenges and give an overview of its data model, the CaosDB Server and its easy-to-learn CaosDB Query Language. We briefly discuss the status of the implementation, how we currently use CaosDB, and how we plan to use and extend it.
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  • Journal Article

    MP2RAGE multispectral voxel‐based morphometry in focal epilepsy 

    Kotikalapudi, Raviteja; Martin, Pascal; Erb, Michael; Scheffler, Klaus; Marquetand, Justus; Bender, Benjamin; Focke, Niels K.
    Human Brain Mapping 2019; 40(17) p.5042-5055
    We assessed the applicability of MP2RAGE for voxel-based morphometry. To this end, we analyzed its brain tissue segmentation characteristics in healthy subjects and the potential for detecting focal epileptogenic lesions (previously visible and nonvisible). Automated results and expert visual interpretations were compared with conventional VBM variants (i.e., T1 and T1 + FLAIR). Thirty-one healthy controls and 21 patients with focal epilepsy were recruited. 3D T1-, T2-FLAIR, and MP2RAGE images (consisting of INV1, INV2, and MP2 maps) were acquired on a 3T MRI. The effects of brain tissue segmentation and lesion detection rates were analyzed among single- and multispectral VBM variants. MP2-single-contrast gave better delineation of deep, subcortical nuclei but was prone to misclassification of dura/vessels as gray matter, even more than conventional-T1. The addition of multispectral combinations (INV1, INV2, or FLAIR) could markedly reduce such misclassifications. MP2 + INV1 yielded generally clearer gray matter segmentation allowing better differentiation of white matter and neighboring gyri. Different models detected known lesions with a sensitivity between 60 and 100%. In non lesional cases, MP2 + INV1 was found to be best with a concordant rate of 37.5%, specificity of 51.6% and concordant to discordant ratio of 0.60. In summary, we show that multispectral MP2RAGE VBM (e.g., MP2 + INV1, MP2 + INV2) can improve brain tissue segmentation and lesion detection in epilepsy.
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  • Journal Article

    Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study 

    Wachter, Rolf; Senni, Michele; Belohlavek, Jan; Straburzynska‐Migaj, Ewa; Witte, Klaus K.; Kobalava, Zhanna; Fonseca, Candida; Goncalvesova, Eva; Cavusoglu, Yuksel; Fernandez, Alberto; et al.
    Chaaban, SaidBøhmer, EllenPouleur, Anne‐CatherineMueller, ChristianTribouilloy, ChristopheLonn, EvaA.L. Buraiki, JehadGniot, JacekMozheiko, MariaLelonek, MalgorzataNoè, AdeleSchwende, HeikeBao, WeibinButylin, DmytroPascual‐Figal, DomingoGniot, JacekMozheiko, MariaLelonek, MalgorzataDominguez, Antonio ReyesHoracek, Thomasdel Rio, Enrique GarciaKobalava, ZhannaMueller, Christian EugenCavusoglu, YukselStraburzynska-Migaj, EwaSlanina, Miroslavvom Dahl, JuergenSenni, MicheleRyding, AlisdairMoriarty, AndrewRobles, Manuel BeltranVillota, Julio NunezQuintana, Antonio GarciaNitschke, ThorstenManuel Garcia Pinilla, JoseBonet, Luis AlmenarChaaban, SaidFilali zaatari, MD, SamiaSpinar, JindrichMusial, WlodzimierzAbdelbaki, KhaledBelohlavek, JanFehske, WolfgangBott, Michael CarlosHoegalmen, GeirLeiro, Marisa CrespoOzcan, Ismail TurkayMullens, WilfriedKryza, RadimAl-Ani, RiadhLoboz-Grudzien, KrystynaErmoshkina, LyudmilaHojerova, SilviaFernandez, Alberto AlfredoSpinarova, LenkaLapp, HaraldBulut, EfraimAlmeida, FilipaVishnevsky, AlexanderBelicova, MargitaPascual, DomingoWitte, KlausWong, KennethDroogne, WalterDelforge, MarcPeterka, MartinOlbrich, Hans‐GeorgCarugo, StefanoNessler, JadwigaMcGill, Thao HuynhHuegl, BurkhardAkin, IbrahimMoreira, IlidioBaglikov, AndreyThambyrajah, JeetendraHayes, ChrisBarrionuevo, Marcelo RaulYigit, ZerrinKaya, HakkiKlimsa, ZdenekRadvan, MartinKadel, ChristophLandmesser, UlfDi Tano, GiuseppeLisik, Malgorzata BuksinskaFonseca, CandidaOliveira, LuisMarques, IreneSantos, Luis MiguelLenner, EgonLetavay, PeterBueno, Manuel GomezMota, PaulaWong, AaronBailey, KristianFoley, PaulHasbani, EduardoVirani, SeanMassih, Tony AbdelAl‐Saif, ShukriTaborsky, MilosKaislerova, MartaMotovska, ZuzanaPrahaCohen, Aron ArielLogeart, DamienEndemann, DierkFerreira, DanielBrito, DulceKycina, PeterBollano, EntelaBasilio, Enrique GalveRubio, Lorenzo FacilaAguado, Marcos GarciaSchiavi, Lilia BeatrizZivano, Daniel FranciscoLonn, EvaSayed, Ali ElPouleur, Anne‐CatherineHeyse, AlexSchee, AlexandrPolasek, RostislavHoura, MarekTribouilloy, ChristopheSeronde, Marie FranceGalinier, MichelNoutsias, MichelSchwimmbeck, PeterVoigt, IngoWestermann, DirkPulignano, GiovanniVegsundvaag, JohnnyAlexandre Da Silva Antunes, JoseMonteiro, PedroStevlik, JanGoncalvesova, EvaHulkoova, BeataJuan Castro Fernandez, AntonioDavies, CeriSquire, IainMeyer, PhilippeSheppard, RichardSahin, TayfunSochor, KarelDe Geeter, GuillaumeWachter, RolfSchmeisser, AlexanderWeil, JoachimSoares, Ana OliveiraVasilevna, Olga BulashovaOshurkov, AndreySunderland, Shahid JunejoGlover, JasonExequiel, TomasDecoulx, EricMeyer, SvenMuenzel, ThomasFrioes, FernandoArbolishvili, GeorgyTokarcikova, AnnaKarlstrom, PatricCarles Trullas Vila, JoanPerez, Gonzalo PenaSankaranarayanan, RajivNageh, ThuraiaAlasia, Diego CristianRefaat, MarwanDemirkan, BurcuAl-Buraiki, JehadKarabsheh, Shadi
    European Journal of Heart Failure 2019; 21(8) p.998-1007
    AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02661217. © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons
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  • Journal Article

    Strategy to enhance transgene expression in proximity of amyloid plaques in a mouse model of Alzheimer's disease 

    Weber-Adrian, Danielle; Kofoed, Rikke Hahn; Chan, Josephine Wing Yee; Silburt, Joseph; Noroozian, Zeinab; Kügler, Sebastian; Hynynen, Kullervo; Aubert, Isabelle
    Theranostics 2019; 9(26) p.8127-8137
    Gene therapy can be designed to efficiently counter pathological features characteristic of neurodegenerative disorders. Here, we took advantage of the glial fibrillary acidic protein (GFAP) promoter to preferentially enhance transgene expression near plaques composed of amyloid-beta peptides (Aβ), a hallmark of Alzheimer’s disease (AD), in the TgCRND8 mouse model of amyloidosis. Methods: The delivery of intravenously injected recombinant adeno-associated virus mosaic serotype 1/2 (rAAV1/2) to the cortex and hippocampus of TgCRND8 mice was facilitated using transcranial MRI-guided focused ultrasound in combination with microbubbles (MRIgFUS), which transiently and locally increases the permeability of the blood-brain barrier (BBB). rAAV1/2 expression of the reporter green fluorescent protein (GFP) under a GFAP promoter was compared to GFP expression driven by the constitutive human beta actin (HBA) promoter. Results: MRIgFUS targeting the cortex and hippocampus facilitated the entry of rAAV1/2 and GFP expression under the GFAP promoter was localized to GFAP-positive astrocytes. Adjacent to Aβ plaques where GFAP is upregulated, the volume, surface area, and fluorescence intensity of the transgene GFP were greater in rAAV1/2-GFAP-GFP compared to rAAV1/2-HBA-GFP treated animals. In peripheral organs, GFP expression was particularly strong in the liver, irrespective of the promoter. Conclusion: The GFAP promoter enhanced transgene expression in proximity of Aβ plaques in the brain of TgCRND8 mice, and it also resulted in significant expression in the liver. Future gene therapies for neurological disorders could benefit from using a GFAP promoter to regulate transgene expression in response to disease-induced astrocytic reactivity.
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  • Journal Article

    A facile oxygen-17 NMR method to determine effective viscosity in dilute, molecularly crowded and confined aqueous media 

    Rezaei-Ghaleh, Nasrollah; Munari, Francesca; Becker, Stefan; Assfalg, Michael; Griesinger, Christian
    Chemical Communications 2019; 55(82) p.12404-12407
    We present an NMR method based on natural abundance 17O relaxation of water to determine effective viscosity in biological aqueous samples. The method accurately captures viscosity of dilute and crowded protein solutions and offers a fairly simple way to quantify the internal fluidity of biological condensates formed through phase separation.
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  • Journal Article

    Real‐time multi‐directional flow MRI using model‐based reconstructions of undersampled radial FLASH – A feasibility study 

    Kollmeier, Jost M.; Tan, Zhengguo; Joseph, Arun A.; Kalentev, Oleksandr; Voit, Dirk; Merboldt, K. Dietmar; Frahm, Jens
    NMR in Biomedicine: Art. ;e4184
    The purpose of this work was to develop an acquisition and reconstruction technique for two- and three-directional (2d and 3d) phase-contrast flow MRI in real time. A previous real-time MRI technique for one-directional (1d) through-plane flow was extended to 2d and 3d flow MRI by introducing in-plane flow sensitivity. The method employs highly undersampled radial FLASH sequences with sequential acquisitions of two or three flow-encoding datasets and one flow-compensated dataset. Echo times are minimized by merging the waveforms of flow-encoding and radial imaging gradients. For each velocity direction individually, model-based reconstructions by regularized nonlinear inversion jointly estimate an anatomical image, a set of coil sensitivities and a phase-contrast velocity map directly. The reconstructions take advantage of a dynamic phase reference obtained by interpolating consecutive flow-compensated acquisitions. Validations include pulsatile flow phantoms as well as in vivo studies of the human aorta at 3 T. The proposed method offers cross-sectional 2d and 3d flow MRI of the human aortic arch at 53 and 67 ms resolution, respectively, without ECG synchronization and during free breathing. The in-plane resolution was 1.5 × 1.5 mm2 and the slice thickness 6 mm. In conclusion, real-time multi-directional flow MRI offers new opportunities to study complex human blood flow without the risk of combining differential phase (i.e., velocity) information from multiple heartbeats as for ECG-gated data. The method would benefit from a further reduction of acquisition time and accelerated computing to allow for extended clinical trials.
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  • Journal Article

    The spectrum of involuntary vocalizations in humans: A video atlas 

    Mainka, Tina; Balint, Bettina; Gövert, Felix; Kurvits, Lille; Riesen, Christoph; Kühn, Andrea A.; Tijssen, Marina A.J.; Lees, Andrew J.; Müller‐Vahl, Kirsten; Bhatia, Kailash P.; et al.
    Ganos, Christos
    Movement Disorders
    Left ventricular assist device (LVAD) therapy is a promising option for patients with advanced heart failure (HF), refractory to guideline‐mandated medical treatment either as a bridge to heart transplantation or as lifelong therapy. Functional capacity improves after LVAD implantation but remains reduced in patients with long‐term LVAD therapy. Exercise training (ET) improves functional capacity and quality of life (QoL) in HF and may provide incremental benefits in patients supported with LVAD therapy. Methods The primary objective of Ex‐VAD is to investigate whether a 12‐week supervised ET can improve peak oxygen uptake (peakVO2) measured by cardiopulmonary exercise testing (CPET) on an ergometer. The study is powered to demonstrate a group difference of 3 mL/min/kg in peakVO2 at week 12, with a power of 0.9 and a standard deviation of 5 mL/min/kg. After baseline assessments to determine whether ET is safe, 66 patients at six trial sites with advanced HF and LVAD therapy will be randomized 2:1 to supervised ET or to the control arm of usual care alone. Patients randomized to ET will perform supervised aerobic endurance and resistance ET (three times/week) for 12 weeks. At baseline and during follow‐up, anthropometry, CPET, echocardiography (at rest and exercise), and QoL evaluation will be performed. Blood samples will be collected to examine cardiac‐specific relevant biomarkers. Overall physical activity, training sessions, and adherence will be monitored and documented throughout the study using accelerometers and patient diaries. Conclusions The Ex‐VAD trial will assess the effects of a supervised ET programme on peakVO2 and QoL in patients with LVAD. As LVAD therapy moves from crisis support to ambulatory functional enhancement, this trial will provide a rationale to improve functional capacity and, in perspective, cardiovascular outcomes in LVAD‐supported patients with advanced HF.
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  • Journal Article

    Exercise training in patients with a left ventricular assist device (Ex‐VAD): rationale and design of a multicentre, prospective, assessor‐blinded, randomized, controlled trial 

    Bobenko, Anna; Schoenrath, Felix; Knierim, Jan H.; Friede, Tim; Verheyen, Nicolas; Mehra, Mandeep R.; Haykowsky, Mark; Herrmann‐Lingen, Christoph; Duvinage, André; Pieske‐Kraigher, Elisabeth; et al.
    Halle, MartinFalk, VolkmarPieske, BurkertEdelmann, Frank
    European Journal of Heart Failure 2019; 21(9) p.1152-1159
    AIMS: Left ventricular assist device (LVAD) therapy is a promising option for patients with advanced heart failure (HF), refractory to guideline-mandated medical treatment either as a bridge to heart transplantation or as lifelong therapy. Functional capacity improves after LVAD implantation but remains reduced in patients with long-term LVAD therapy. Exercise training (ET) improves functional capacity and quality of life (QoL) in HF and may provide incremental benefits in patients supported with LVAD therapy. METHODS: The primary objective of Ex-VAD is to investigate whether a 12-week supervised ET can improve peak oxygen uptake (peakVO2 ) measured by cardiopulmonary exercise testing (CPET) on an ergometer. The study is powered to demonstrate a group difference of 3 mL/min/kg in peakVO2 at week 12, with a power of 0.9 and a standard deviation of 5 mL/min/kg. After baseline assessments to determine whether ET is safe, 66 patients at six trial sites with advanced HF and LVAD therapy will be randomized 2:1 to supervised ET or to the control arm of usual care alone. Patients randomized to ET will perform supervised aerobic endurance and resistance ET (three times/week) for 12 weeks. At baseline and during follow-up, anthropometry, CPET, echocardiography (at rest and exercise), and QoL evaluation will be performed. Blood samples will be collected to examine cardiac-specific relevant biomarkers. Overall physical activity, training sessions, and adherence will be monitored and documented throughout the study using accelerometers and patient diaries. CONCLUSIONS: The Ex-VAD trial will assess the effects of a supervised ET programme on peakVO2 and QoL in patients with LVAD. As LVAD therapy moves from crisis support to ambulatory functional enhancement, this trial will provide a rationale to improve functional capacity and, in perspective, cardiovascular outcomes in LVAD-supported patients with advanced HF.
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  • Journal Article

    The clinical significance of interleukin‐6 in heart failure: results from the BIOSTAT‐CHF study 

    Markousis‐Mavrogenis, George; Tromp, Jasper; Ouwerkerk, Wouter; Devalaraja, Matt; Anker, Stefan D.; Cleland, John G.; Dickstein, Kenneth; Filippatos, Gerasimos S.; Harst, Pim; Lang, Chim C.; et al.
    Metra, MarcoNg, Leong L.Ponikowski, PiotrSamani, Nilesh JZannad, FaiezZwinderman, Aeilko H.Hillege, Hans L.Veldhuisen, Dirk J.Kakkar, RahulVoors, Adriaan A.Meer, Peter
    European Journal of Heart Failure 2019; 21(8) p.965-973: Art.
    AIMS: Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. METHODS AND RESULTS: Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models. CONCLUSIONS: In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations.
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  • Journal Article

    Spontaneous Left Cardiac Isomerism in Chick Embryos: Case Report, Review of the Literature, and Possible Significance for the Understanding of Ventricular Non-Compaction Cardiomyopathy in the Setting of Human Heterotaxy Syndromes 

    Männer, Jörg
    Journal of Cardiovascular Development and Disease 2019; 6(4): Art. 40
    The outer shape of most vertebrates is normally characterized by bilateral symmetry. The inner organs, on the other hand, are normally arranged in bilaterally asymmetric patterns. Congenital deviations from the normal organ asymmetry can occur in the form of mirror imagery of the normal arrangement (situs inversus), or in the form of arrangements that have the tendency for the development of bilateral symmetry, either in a pattern of bilateral left-sidedness (left isomerism) or bilateral right-sidedness (right isomerism). The latter two forms of visceral situs anomalies are called “heterotaxy syndromes”. During the past 30 years, remarkable progress has been made in uncovering the genetic etiology of heterotaxy syndromes. However, the pathogenetic mechanisms causing the spectrum of cardiovascular defects found in these syndromes remain poorly understood. In the present report, a spontaneous case of left cardiac isomerism found in an HH-stage 23 chick embryo is described. The observations made in this case confirmed the existence of molecular isomerism in the ventricular chambers previously noted in mouse models. They, furthermore, suggest that hearts with left cardiac isomerism may have the tendency for the development of non-compaction cardiomyopathy caused by defective development of the proepicardium.
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  • Journal Article

    The Calmodulin Binding Region of the Synaptic Vesicle Protein Mover Is Required for Homomeric Interaction and Presynaptic Targeting 

    Akula, Asha Kiran; Zhang, Xin; Viotti, Julio S.; Nestvogel, Dennis; Rhee, Jeong-Seop; Ebrecht, Rene; Reim, Kerstin; Wouters, Fred; Liepold, Thomas; Jahn, Olaf; et al.
    Bogeski, IvanDresbach, Thomas
    Frontiers in Molecular Neuroscience 2019; 12: Art. 249
    Neurotransmitter release is mediated by an evolutionarily conserved machinery. The synaptic vesicle (SV) associated protein Mover/TPRGL/SVAP30 does not occur in all species and all synapses. Little is known about its molecular properties and how it may interact with the conserved components of the presynaptic machinery. Here, we show by deletion analysis that regions required for homomeric interaction of Mover are distributed across the entire molecule, including N-terminal, central and C-terminal regions. The same regions are also required for the accumulation of Mover in presynaptic terminals of cultured neurons. Mutating two phosphorylation sites in N-terminal regions did not affect these properties. In contrast, a point mutation in the predicted Calmodulin (CaM) binding sequence of Mover abolished both homomeric interaction and presynaptic targeting. We show that this sequence indeed binds Calmodulin, and that recombinant Mover increases Calmodulin signaling upon heterologous expression. Our data suggest that presynaptic accumulation of Mover requires homomeric interaction mediated by regions distributed across large areas of the protein, and corroborate the hypothesis that Mover functionally interacts with Calmodulin signaling.
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